Chronic fatigue syndrome (CFS) and fibromyalgia (FM) have been considered diagnoses of exclusion where no other diagnosis fit well. CFS has been defined by specific requirements of fatigue, its duration, associated symptoms, and initial clinical and laboratory evaluation. There has existed no reliable laboratory means for determining whether an individual was suffering from CFS, FM, or some other disease. Accordingly, a felt need for a method of testing for CFS and FM existed.
This invention relates to a method for using a novel combination of assays to detect minimal activation of the coagulation response for determining whether a patient whose initial clinical evaluation indicates chronic fatigue syndrome, fibromyalgia, and related conditions can be treated using anticoagulant therapies. If activation of the coagulation response is detected, the present invention further includes treatment of CFS, FM or related condition using anticoagulant therapies.
We have discovered that we may reliably diagnose a patient suffering from CFS or FM by evaluating the status of the coagulation response in that patient by using a novel combination of tests which can detect minimal activation of the coagulation response in a patient. This novel combination includes tests for determining levels of fibrinogen, prothrombin fragment 1+2, thrombin/antithrombin complexes, soluble fibrin monomer, and platelet activation by flow cytometry. These assays are highly sensitive to minimal deviation from normal. Deviation from the normal values in any two of the five assays permits diagnosis of CFS, FM, or other disease associated with activation of the coagulation response.
Once a condition associated with activation of the coagulation response has been diagnosed, the patient is treated with anticoagulant therapy, such as heparin followed by warfarin or warfarin alone. Coumarins or coumarin derivatives may also be used. Heparin can be defined as heparin (porcine or bovine) or any of its derivatives, such as low molecular weight heparin (LMWH), oral heparin, heparinoids, or any other designer heparin-like drugs. It is presently preferred that a low dose anticoagulant therapy be used. Patient progression and recovery is then monitored using the novel combination of assays.
We postulate that a majority of individuals diagnosed as CFS and/or FM on clinical criteria may be defined as having antiphospholipid antibody syndrome (APS) with endothelial cells as a major disease target with or without platelet activation. Laboratory findings in patients suffering with APS include anticardiolipin antibodies, lupus anticoagulants, antiphosphatidylserine antibodies, anti-B2GPI antibodies. Clinical findings include thrombocytopenia, neurological complications, venous thrombosis, arterial thrombosis, and/or recurrent fetal loss. Patients with primary APS (PAPS) presently have no clinical or laboratory evidence of another definable autoimmune disease. Antiphospholipid antibodies have long been associated with a hypercoagulable state, involving both procoagulant activity as well as inhibition of anticoagulant and fibrinolytic activity. In CFS and/or FM patients, the principal antibodies found to date are the anti-B2GPI antibodies. This precedes the generation of a hypercoagulable state based on our proposed model.
Endothelial cells are protected in the microvascular circulation by B2GPI and Annexin V proteins. This protective layer helps endothelial cells maintain an anticoagulant environment. Exposure to pathogens, such as herpes viruses (HV, HHV6, EBV), cytomegalovirus (CMV), mycoplasma, chlamydia pneumonia, or some vaccines can result in both active persistent infection and latent infection in mononuclear and endothelial cells. Some pathogens like CMV and HV constitutively express phosphatidylserine-like procoagulant activity, capable of binding Xa and Va to form the prothrombinase complex. HHV6 is found in about 70% of all CFS patients. In several studies, this same 70% infection rate is seen in multiple sclerosis patients with HHV6. HHV6 is also implicated in chronic myelopathy. Endothelial cells serve as a reservoir for harboring HHV6. Infected endothelial cells lose the ability to synthesize prostacyclin with associated incapacity to deter platelet adhesion. In addition, CMV and HV express tissue factor antigen on each virus surface. HV can induce a prothrombotic phenotype in vascular endothelial cells. This phenotype markedly reduces heparin sulfate protcoglycan synthesis and surface expression by endothelial cells. Thrombomodulin expression is also reduced in infected endothelium. Due to fibrin deposition, fibrinolysis activation may also be diminished. Activation of endothelial cells is seen by surface expression of P-selectin and von Willebrand Factor (vWF). Thrombin generated after the assembly of the prothrombinase complex on the virus-infected endothelium mobilizes vWF from the Weibel-Palade body to the endothelial cell surface, where it acts as a platelet receptor. Cell-independent thrombin generation may be the earliest event in vascular pathology mediated by HV.
Because exposure and expression of phosphatidylserine (PS) is part of the infectious process, those exposed phospholipids activate the immune system to form antiphospholipid antibodies. The primary targets of these immunoglobulin (Ig)G, IgM and IgA antibodies are the protective proteins for endothelial cells, specifically B2GPI and Annexin V. As with other APS diseases, there is an increased incidence of thrombocytopenia in HHV6 patients. With the loss of this protective layer due to APL antibodies, coagulation proteins can bind, react and form thrombin (IIa). If this process is not property inhibited (thrombin-anti-thrombin complexes), then excess thrombin can convert fibrinogen to soluble fibrin monomer (SFM). SFM is a sticky protein that increases blood viscosity and can coat endothelial cells surfaces as fibrin or fibrinoid material. Patients with CFS and FM symptoms typically have a hypercoagulable state demonstrated by increased markers of coagulation activation and increased blood viscosity due to the generation of soluble fibrin monomer (SFM). Once CFS and FM is diagnosed using our combination of assays, CFS/FM patients may be treated with anticoagulant therapies, and their treatment and recovery monitored using our combination of tests.
Patients with immune mediated chronic inflammatory disorders of many types can have low level activation of the coagulation response. Therefore, patients with a spectrum of chronic inflammatory processes may have low level activation of coagulation as part of their pathophysiology. We postulate that our tests for activation of the coagulation and platelet systems also have application to other conditions which stem from activation of the coagulation response. This has been validated by preliminary studies of patients suffering with multiple sclerosis, breast implant sickness syndrome, fetal wastage syndrome, gulf war illness, inflammatory bowel disease, autism. As with CFS and FM, once diagnosed using our combination of assays, these patients may be treated with anticoagulant therapies, and their treatment and recovery monitored using our combination of tests.
We postulate that our combination of tests for detecting minimal activation of coagulation response also has application to detecting and treating, Sjogrens syndrome, late Lyme disease (also called chronic Lyme disease), transient ischemic attack, attention deficit disorder, Alzheimer""s disease, Parkinson""s disease, as well as some cardiovascular diseases. Once diagnosed using our combination of assays, these patients should also benefit from treatment with anticoagulant therapies, and their treatment and recovery monitored using our combination of tests.
Although thrombin generation is among the first steps in the coagulation response, thrombin itself is difficult to quantify because it lasts only 30 seconds in the blood circulation. Consequently, other measurable components of the coagulation response must be considered. (1) Prothrombin fragment 1+2, which is released when prothrombin is converted into thrombin, can be used to indicate activation of the coagulation response. (2) Increased levels of thrombin/antithrombin complexes (TATs) also indicate thrombin generation and an attempt to remove excess thrombin. Thus, an increased level of TATs also indicates activation of the coagulation response. (3) When excess thrombin is generated by the coagulation response, fibrinogen is cleaved to soluble fibrin monomer (SFM). Accordingly, increased levels of SFM also indicate activation of the coagulation response. (4) With the consumption of fibrinogen, the body may compensate by increasing fibrinogen levels slightly above the normal range; therefore, increased fibrinogen levels are also an indicator of activation of the coagulation response. (5) Finally, platelet activation may also be used as an indicator of coagulation response activation.
The tests discussed above are the assays presently preferred, it being understood that other tests sensitive to minimal activation of the coagulation response may be substituted for the assays discussed.